The prostaglandins are extremely potent substances which produce a wide variety of biological effects, often in the nanomolar to picomolar concentration range. The discovery of two forms of prostaglandin endoperoxide H synthase, PGHS-1 and PGHS-2, that catalyze the oxidation of arachidonic acid leading to prostaglandin biosynthesis has resulted in renewed research to delinate the role of these two isozymes in physiology and pathophysiology. These isozymes have been shown to have different gene regulation and represent distinctly different prostaglandin biosynthesis pathways. The PGHS-1 pathway is expressed constitutively in most cell types. It responds to produce prostaglandins that regulate acute events in vascular homeostasis and also has a role in maintaining normal stomach and renal function. The newly discovery PGHS-2 pathway involves an induction mechanism which has been liked to inflammation, mitogenesis and ovulation phenomena.
Prostaglandin inhibitors provide therapy for pain, fever, and inflammation, and are useful therapies, for example, in the treatment of rheumatoid arthritis and osteoarthritis. The non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, naproxen and the fenamates inhibit both isozymes, prostaglandin endoperoxide H synthase 1 (PGHS-1) and prostaglandin endoperoxide H synthase 2 (PGHS-2). Inhibition of the constitutive enzyme PGHS-1 results in gastrointestinal side effects including ulcers and bleeding and incidence of renal problems with chronic therapy. Inhibitors of the induced isozyme PGHS-2 are proposed to provide antiinflammatory activity without the side effects of PGHS-1 inhibitors. A general review of the current knowledge of PGHS-1 and PGHS-2 isozyme properties and a summary of inhibitors and their activity is provided by:
(1) Battistini, B.; Botting, R.; Bakhle, Y. S. COX-1 and COX-2: toward the development of more selective NSAIDs, Drug New and Perspectives 1994, 7(8), 501-512. PA1 (2) DeWitt, D. L.; Bhattacharyya, D.; Lecomte, M.; Smith, W. L. The differenctial susceptibility of prostaglandin endoperoxide H synthases-1 and -2 to nonsteroidal anti-inflammatory drugs: aspirin derivatives as selective inhibitors. Med. Chem. Res. 1995, 5(5), 325-343. PA1 (3) Mitchell, J. A.; Larkin, S.; Williams, T. J. Cyclooxygenase-2: regulation and relevance in inflammation. Biochem. Pharm. 1995, 50(10), 1535-1542.
Fenamate compounds were developed as prostaglandin biosynthesis inhibitors prior to the discovery of the different isozyme forms. The reported fenamates (Scherrer, R. A. Fenamic acids, in "Anti-inflammatory and anti-rheumatic drugs", Vol II, Rainsford, K. D. ed., CRC Press, Boca Raton, Fla., 1985, Chapter 4, pp 65-85) include: diclofenac, meclofenamic acid, mefenamic acid, flufenamic acid, and tolfenamic acid. Meclofenamic acid, a representative fenamate NSAID, has been reported to inhibit both PGHS-1 and PGHS-2 (Battistini, B.; Botting, R.; Bakhle, Y. S. COX-1 and COX-2: toward the development of more selective NSAIDs, Drug New and Perspectives 1994, 7(8), 501-512.)